Nicotine reinforcement may stem partly from its complex interoceptive stimulus effects. Although traditional subjective effects measures may be useful in assessing these effects in humans, drug discrimination techniques could provide additional, and possibly more reliable, understanding of the interoceptive stimulus effects of nicotine. Formal drug discrimination procedures have been used in animal research on nicotine but very rarely with humans. The present proposal seeks to programmatically examine the discriminative stimulus effects of nicotine per se in male and female subjects. In each study, subjects will initially be trained to discriminate nicotine from saline placebo (discrimination training and testing), using a measured-dose nasal spray dosing procedure, and will subsequently be tested on their responding to a range of nicotine doses (generalization testing). Alterations in generalization test responding due to various conditions which commonly accompany tobacco smoking (e.g. concurrent alcohol intake; see below) will indicate the degree to which these conditions influence the stimulus effects of nicotine and, possibly, nicotine intake. Specifically, we will: 1) examine the reliability of nicotine discrimination and verify that this discrimination is due to nicotine per se by comparing responses with vs. without pre-treatment with mecamylamine, a nicotinic cholinergic receptor blocker, 2) compare sensitivity of nicotine discrimination between smokers and nonsmokers to determine the influence of long-term exposure on discrimination, 3) relate nicotine discrimination to nicotine choice behavior to help assess the relevance of nicotine discrimination to its abuse liability, 4) examine the effect of the initial training dose on subsequent responding during generalization testing, 5) identify whether pre-treatment with nicotine (via transdermal nicotine patch) reduces sensitivity to the discriminative stimulus effects of nicotine, suggesting acute tolerance to these effects, and 6) determine alterations in the discriminative stimulus effects of nicotine due to concurrent consumption of caffeine and alcohol. Results of this research should enhance our knowledge of the stimulus effects of nicotine in humans and the influence of certain conditions on these effects. Findings may also provide directions for future research into comparing the stimulus effects of nicotine with those of other drugs (e.g. caffeine), the link between these effects and nicotine dependence, and the influence of various nicotine treatments on altering nicotine discrimination.